Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphospate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Accordingly, inhibitors of these tyrosine kinases are useful for the prevention and treatment chemotherapy of proliferative diseases dependent on these enzymes.
For example, a method of treatment described herein relates to neoangiogenesis. Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.
Vascular endothelial growth factor (VEGF) binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1. Cell culture and gene knockout experiments indicate that each receptor contributes to different aspects of angiogenesis. KDR mediates the mitogenic function of VEGF whereas Flt-1 appears to modulate non-mitogenic functions such as those associated with cellular adhesion. Inhibiting KDR thus modulates the level of mitogenic VEGF activity.
Vascular growth in the retina leads to visual degeneration culminating in blindness. VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy. Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased pO2 levels in mice that lead to neovascularization. Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.
Expression of VEGF is also significantly increased in hypoxic regions of animal and human tumors adjacent to areas of necrosis. Monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities. These monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells. Viral expression of a VEGF-binding construct of Flk-1, the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors. Embryonic stem cells, which normally grow as solid tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors. Inhibition of KDR or Flt-1 is implicated in pathological neoangiogenesis, and these are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., diabetic retinal vascularization, as well as various forms of cancer.
Cancers which are treatable in accordance with the present invention demonstrate high levels of gene and protein expression. Examples of such cancers include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, atherosclerosis, diabetic retinopathy or inflammatory diseases, in mammals.
A compound is disclosed in accordance with formula Ia: 
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X is N or C;
R1andR3 are independently H, C1-10 alkyl, C3-6 cycloalkyl, C5-10 aryl, halo, OH, C3-10 heterocyclyl, or C5-10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is independently H, C1-6 alkyl C5-10 aryl, C3-6 cycloalkyl, OH, NO2, xe2x80x94NH2, or halogen;
R4andR5 are independently H, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkoxy C2-10 alkenyl, C2-10 alkynyl, C5-10 aryl, C3-10 heterocyclyl, C1-6 alkoxyNR7R8, halo, NO2, OH, xe2x80x94NH2 or C5-10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra, or R4 and R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from Ra.
Ra is H, C1-10 alkyl, halogen, NO2, R, NHC1-6 alkylR9, OR, xe2x80x94NR, RNR7R8, NR7R8, R7R8, CN, C5-10 aryl, C5-10 heteroaryl or C3-10 heterocyclyl;
R is H, C1-6 alkyl or C1-6 alkylR9;
R9 is C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and
R7andR8 are independently H, C1-10 alkyl, C3-6 cycloalkyl, COR, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
Further compounds are disclosed in accordance with formula I: 
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X is N or C;
R1 is H, C1-10 alkyl, C3-6 cycloalkyl, C5-10 aryl, halo, OH, C3-10 heterocyclyl, or C5-10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2andR3 are independently H, C1-6 alkyl, C5-10 aryl, C3-6 cycloalkyl, OH, NO2, xe2x80x94NH2, or halogen;
R4 is H, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkoxy C2-10 alkenyl, C2-10 alkynyl, C5-10 aryl, C3-10 heterocyclyl, C1-6 alkoxyNR7R8, NO2, OH, xe2x80x94NH2 or C5-10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R5 is H, or C 1-6 alkyl, OR, halo, NH2 or NO2;
Ra is H, C1-0 alkyl, halogen, NO2, OR, xe2x80x94NR, NR7R8, R7R8, C5-10 aryl, C5-10 heteroaryl or C3-10 heterocyclyl;
R is H, or C1-6 alkyl, C1-6 alkylR9;
R9 is C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl; and
R7andR8 are independently H, C1-10 alkyl, C3-6 cycloalkyl, COR, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
Also disclosed is a pharmaceutical composition which is comprised of a compound represented by the formula I: 
wherein R1, R2, R3, R4 and R5 are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
Also included is a method of treating or preventing a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.
Also included is a method of treating or preventing cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.
Also included in the present invention is a method of treating or preventing diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis.
More particularly, a method of treating or preventing ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
More particularly, a method of treating or preventing retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization. Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology. Also included is a method of treating or preventing age-related macular degeneration.
These and other aspects of the invention will be apparent from the teachings contained herein.
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.
Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following: 
herein: x plus y=from 0-10; and w plus z=from 0-9.
The alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of Ra, described herein.
The term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of Ra, when a substituted alkenyl group is provided.
The term xe2x80x9calkynylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of Ra, when a substituted alkynyl group is provided.
Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like. Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted with 1-3 groups of Ra as defined herein. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
The term heterocycle, heteroaryl, heterocyclyl or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of Ra. Examples of such heterocyclic elements, inclusive of all possible isomers, include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.
The term xe2x80x9calkoxyxe2x80x9d refers to those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
The term xe2x80x9chalogenxe2x80x9d is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds which are drug precursors which, following administration and absorption, release the drug in vivo via some metabolic process. Exemplary prodrugs include acyl amides of the amino compounds of this inventon such as amides of alkanoic(C1-6)acids, amides of aryl acids (e.g., benzoic acid) and alkane(C1-6)dioic acids.
Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant tyrosine kinase enzyme activity. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), etc.
One embodiment of the present invention is in accordance with formula Ia: 
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X is N or C;
R1andR3 are independently H, C1-10 alkyl, C3-6 cycloalkyl, C5-10 aryl, halo, OH, C3-10 heterocyclyl, or C5-10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is independently H, C1-6 alkyl, C5-10 aryl, C3-6 cycloalkyl, OH, NO2, xe2x80x94NH2, or halogen;
R4andR5 are independently H, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkoxy C2-10 alkenyl, C2-10 alkynyl, C5-10 aryl, C3-10 heterocyclyl, C1-6 alkoxyNR7R8, halo, NO2, OH, xe2x80x94NH2 or C5-10 heteroaryl, said allyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra, or R4 and R5 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing one to three additional heteroatoms selected from the group consisting of N, O and S, which can be optionally substituted with from one to three members selected from Ra.
Ra is H, C1-10 alkyl, halogen, NO2, R, NHCl1-6 alkylR9, OR, xe2x80x94NR, RNR7R8, NR7R8, R7R8, CN, C5-10 aryl, C5-10 heteroaryl or C3-10 heterocyclyl;
R is H, C1-6 alkyl or C1-6 alkylR9;
R9 is C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and
R7andR8 are independently H, C1-10 alkyl, C3-6 cycloalkyl, COR, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
An aspect of this invention is described wherein X is C and all other variables are as described above.
Another aspect of this invention is described wherein X is N and all other variables are as described above.
Still another aspect of this invention is described wherein R4 is C1-10 alkyl, C3-6 cycloalkyl, C5-10 aryl, C5-10 heteroaryl, or C3-10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
In yet another aspect, the invention is described wherein R1 is C1-10 alkyl C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
Another aspect of this invention is described wherein Ra is H, C1-10 alkyl, halogen, C1-6 alkylR9, CN, R, OR, NR, RNR7R8, NR7R8, R7R8 and all other variables are as described above.
A preferred subset of compounds of the present invention is realized when:
R1andR3 are independently H, C1-10 alkyl, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is independently H, C1-6 alkyl, C3-6 cycloalkyl, OH, or halogen;
R4andR5 are independently H, C1-10 alkyl, C3-6 cycloalkyl, C5-10 aryl, C5-10 heteroaryl, C3-10 heterocyclyl, C1-6 alkoxyNR7R8, NO2, OH, xe2x80x94NH2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
Another preferred subset of compounds of the present invention is realized when:
R1andR3 are independently C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is H or C1-6 alkyl;
R4 is piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
Another embodiment of the invention is a compound in accordance with formula I: 
X is N or C;
R1 is H, C1-10 alkyl, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2andR3 are independently H, C1-6 alkyl, OH, NO2, xe2x80x94NH2, or halogen;
R4 is C5-10 aryl, C3-10 heterocyclyl, C1-6 alkoxyNR7R8, or C5-10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R5 is H, C1-6 alkyl, OR, halo, NH2 or NO2;
Ra is H, C1-10 alkyl, halogen, NO2, R, OR, xe2x80x94NR, NR7R8, R7R8, C5-10 aryl, C5-10 heteroaryl or C3-10 heterocyclyl,
R is H, or C1-6 alkyl, C1-6 alkylR9;
R9 is C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl; and
R7andR8 are independently H, C1-10 alkyl, C3-6 cycloalkyl, COR, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
An aspect of this invention is described wherein X is C and all other variables are as described above.
Another aspect of this invention is described wherein X is N and all other variables are as described above.
Still another aspect of this invention is described wherein R4 is C1-10 alkyl, C3-6 cycloalkyl, C5-10 aryl, C5-10 heteroaryl, or C3-10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
In yet another aspect, the invention is described wherein R1 is C1-10 alkyl, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
A prefered embodiment of this invention is realized when:
R1 is H, C1-10 alkyl, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl; said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2andR3 are independently H, C1-6 alkyl, C3-6 cycloalkyl, OH, or halogen;
R4 is H, C1-10 alkyl, C3-6 cycloalkyl, C5-10 aryl, C5-10 heteroaryl, C3-10 heterocyclyl, C1-6 alkoxyNR7R8, NO2, OH, xe2x80x94NH2 or said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
Another prefered embodiment of this invention is realized when:
R1 is C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl; said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2andR3 are independently H or C1-6 alkyl;
R4 is C1-10 alkyl, C5-10 aryl, C5-10 heteroaryl, C3-10 heterocyclyl said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and all other variables are as described above.
Still another embodiment of the invention is a compound in accordance with formula IIa: 
or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X and W are independently N or C;
R1andR3 are independently H, C1-10 alkyl, C3-6 cycloalkyl, C5-10 aryl, halo, OH, C3-10 heterocyclyl, or C5-10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R2 is independently H, C1-6 alkyl, C5-10 aryl, C3-6 cycloalkyl, OH, NO2, xe2x80x94NH2, or halogen;
R5 is independently H, C1-10 alkyl, C3-6 cycloalkyl, C1-6 alkoxy C2-10 alkenyl, C2-10 alkynyl, C5-10 aryl, C3-10 heterocyclyl, C1-6 alkoxyNR7R8, halo, NO2, OH, xe2x80x94NH2 or C5-10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
R10 is H, or C1-6 alkyl, C1-6 alkylR9, C5-10 aryl, C3-10 heterocyclyl, NHC1-6 alkylR9, said alkyl (where R is C1-6 alkyl), aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
Ra is H, C1-10 alkyl, halogen, NO2, OR, xe2x80x94NR, RNR7R8, NR7R8, R7R8, CN, C5-10 aryl, C5-10 heteroaryl or C3-10 heterocyclyl;
R is H, C1-6 alkyl or C1-6 alkylR9;
R9 is C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl said aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra; and
R7andR8 are independently H, C1-10 alkyl, C3-6 cycloalkyl, COR, C5-10 aryl, C3-10 heterocyclyl, or C5-10 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
An aspect of this invention is described wherein X or W independently are C and all other variables are as described above.
Another aspect of this invention is described wherein X or W are independently N and all other variables are as described above.
Still another aspect of this invention is described wherein R10 is H, C1-10 alkyl, C1-6 alkylR9, C5-10 aryl, C5-10 heteroaryl, or C3-10 heterocyclyl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra and all other variables are as described above.
Examples of the compounds of this invention are:
1) 1-phenyl-5-(4-methoxyphenyl)benzimidazole,
2) 1-phenyl-5-(4-(2-(1-piperidinyl)ethoxy)phenyl)benzimidazole,
3) 3-phenyl-6-(4-methoxylphenyl)imidazo[4,5-b]pyridine,
4) 3-phenyl-6-(4-(2-(1-piperidinyl)ethoxy)phenyl)imidazo[4,5-b]pyridine,
5) 3-phenyl-6-(4-(2-(1-piperidinyl)ethoxyphenyl)imidazo[4,5-b]pyridine,
6) 3-(2-thiazoyl)-6-(4-(3-(1-piperidinyl)propylphenyl)imidazo[4,5-b]pyridine,
7) 1-(2-thiazoyl)-5-(4-(3-(1-piperidinyl)propyl)phenyl)benzimidazole,
8) 1-(3-thiophenyl)-5-(4-(3-(1-piperidinyl)propyl)phenyl)imidazo[4,5-b]pyridine,
9) 1-(3-thiophenyl)-5-(4-(3-(1-piperidinyl)propyl)phenyl)benzimidazole,
10)3-(3-thiophenyl)-6-(4-(3-(1-piperidinyl)propylphenyl)imidazo[4,5-b]pyridine,
11)1-Phenyl-5-[5-(2-piperidin-1-yl-ethoxy)-pyridin-2-yl]-1H-benzimidazole,
12)1-(4-Cyanophenyl)-5-[6-(2-piperidin-1-yl-ethoxy)-pyridin-3-yl]-1H-benzimidazole,
13)1-Phenyl-5-[6-(2-piperidin-1-yl-ethoxy)-pyridin-3-yl]-1H-benzimidazole,
14)1-(3-Cyanophenyl)-5-[6-(2-piperidin-1-yl-ethoxy)-pyridin-3-yl]-1H-benzimidazole,
15)1-(3-Thiophene)-5-[6-(2-piperidin-1-yl-ethoxy)-pyridin-3-yl]-1H-benzimidazole,
16) [5-(1-Phenyl-1H-benzoimidazol-5-yl)-pyridin-2-yl]-(2-piperidin-1-yl-ethyl)-amine,
17) [5-(1-Phenyl-1H-benzoimidazol-5-yl)-pyridin-2-yl]-(2-morpholin-1-yl-ethyl)-amine,
18) 1-(3-Pyridyl)-5-(4-(2-(1-piperidinyl)ethoxy)phenyl)benzimidazole,
19)4-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one,
20) 4-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-ethyl)-1H-pyridin-2-one,
21) 1-(2-morpholin4-yl-ethyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
22) 1-(3-dimethylamino-propyl)-4-(1-phenyl-1H-benzoimnidazol-5-yl)-1H-pyridin-2-one,
23) 1-(1-methyl-piperidin-3-ylmethyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
24) 1-[3-(4-methylpiperazin-1-yl)-propyl)]-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
25) 1-(2-dimethylamino-propyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
26) 1-(3-dimethylamino-2-methyl-propyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
27) 1-[2-(4-cyano-piperidin-1-yl)-ethyl]-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
28) 1-(3-piperidin-1-yl-propyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
29) 1-(3-piperidin-1-yl-ethyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
30) 1-(2-morpholin-4-yl-ethyl)4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
31) 1-(3-dimethylamino-propyl)4-(1-thiophen-3-yl-1H-benzoimnidazol-5-yl)-1H-pyridin-2-one,
32) 1-(1-methyl-piperidin-3-ylmethyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
33) 1-[3-(4-methylpiperazin-1-yl)-propyl)]4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
34) 1-(2-dimethylamino-propyl)4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
35) 1-(3-dimethylamino-2-methyl-propyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
36) 1-[2-(4-cyano-piperidin-1-yl)-ethyl]-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
37) 5-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one,
38) 5-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-ethyl)-1H-pyridin-2-one,
39) 1-(2-morpholin-4-yl-ethyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
40) 1-(3-dimethylamino-propyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
41) 1-(1-methyl-piperidin-3-ylmethyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
42) 1-[3-(4-methylpiperazin-1-yl)-propyl)]-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
43) 1-(2-dimethylamino-propyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
44) 1-(3-dimethylamino-2-methyl-propyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
45) 1-[2-(4-cyano-piperidin-1-yl)-ethyl]-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
46) 1-(3-piperidin-1-yl-propyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
47) 1-(3-piperidin-1-yl-ethyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
48) 1-(2-morpholin-4-yl-ethyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
49) 1-(3-dimethylamino-propyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
50) 1-(1-methyl-piperidin-3-ylmethyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
51) 1-[3-(4-methylpiperazin-1-yl)-propyl)]-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
52) 1-(2-dimethylamino-propyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
53) 1-(3-dimethylamino-2-methyl-propyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
54)1-[2-(4-cyano-piperidin-1-yl)-ethyl]-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyridin-2-one,
55) 5-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyrimidin-2-one,
56) 5-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-ethyl)-1H-pyrimidin-2-one,
57) 1-(2-morpholin-4-yl-ethyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
58) 1-(3-dimethylamino-propyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
59) 1-(1-methyl-piperidin-3-ylmethyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
60) 1-[3-(4-methylpiperazin-1-yl)-propyl)]-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
61) 1-(2-dimethylamino-propyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
62) 1-(3-dimethylamino-2-methyl-propyl)-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
63) 1-[2-(4-cyano-piperidin-1-yl)-ethyl]-5-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
64) 1-(3-piperidin-1-yl-propyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
65) 1-(3-piperidin-1-yl-ethyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
66) 1-(2-morpholin4-yl-ethyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
67) 1-(3-dimethylamino-propyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
68) 1-(1-methyl-piperidin-3-ylmethyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
69) 1-[3-(4-methylpiperazin-1-yl)-propyl)]-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
70) 1-(2-dimethylamino-propyl)-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
71) 1-(3-dimethylamino-2-methyl-propyl)-5-(1-thiophen-3-yl-1H-benzoimnidazol-5-yl)-1H-pyrimidin-2-one,
72) 1-[2-(4-cyano-piperidin-1-yl)-ethyl]-5-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
73) 4-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyrimidin-2-one,
74) 4-(1-phenyl-1H-benzoimidazol-5-yl)-1-(3-piperidin-1-yl-ethyl)-1H-pyrimidin-2-one,
75) 1-(2-morpholin-4-yl-ethyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
76) 1-(3-dimethylamino-propyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
77) 1-(1-methyl-piperidin-3-ylmethyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
78) 1-[3-(4-methylpiperazin-1-yl)-propyl)]-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
79) 1-(2-dimethylamino-propyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
80) 1-(3-dimethylamino-2-methyl-propyl)-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
81) 1-[2-(4-cyano-piperidin-1-yl)-ethyl]-4-(1-phenyl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
82) 1-(3-piperidin-1-yl-propyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one
83) 1-(3-piperidin-1-yl-ethyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
84) 1-(2-morpholin-4-yl-ethyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
85) 1-(3-dimethylamino-propyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
86) 1-(1-methyl-piperidin-3-ylmethyl)-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
87) 1-[3-(4-methylpiperazin-1-yl)-propyl)]-4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
88) 1-(2-dimethylamino-propyl)4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
89) 1-(3-dimethylamino-2-methyl-propyl)4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
90) 1-[2-(4-cyano-piperidin-1-yl)-ethyl]4-(1-thiophen-3-yl-1H-benzoimidazol-5-yl)-1H-pyrimidin-2-one,
91) 1-(4-Pyridyl)-5-(4-(2-(1-piperidinyl)ethoxy)phenyl)benzimidazole,
92) 1-(3-Pyridyl)-5-[6-(2-piperidin-1-yl-ethoxy)-pyridin-3-yl]-1H-benzimidazole, and
93) 1-(4-Pyridyl)-5-[6-(2-piperidin-1-yl-ethoxy)-pyridin-3-yl]-1H-benzimidazole
or a pharmaceutically acceptable salt, hydrate or prodrug thereof.
The invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with a carrier. As used herein the terms xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d and xe2x80x9chydratesxe2x80x9d refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
When a compound of formula I is present as a salt or hydrate which is non-pharmaceutically acceptable, this can be converted to a salt or hydrate form which is pharmaceutically acceptable in accordance with the present invention.
When the compound is negatively charged, it is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium. Other suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc. An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality. Likewise when the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
Pharmaceutically acceptable salts also include acid addition salts. Thus, the compound can be used in the form of salts derived from inorganic or organic acids or bases. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
The compounds of the present invention, may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. When any variable (e.g., aryl, heterocyle, R1, etc.)occurs more than one time in any constituent or in Formula I, its definition on each occcurence is independent of its definition at every other occurrence, unless otherwise stated.
The compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.
The compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.
Thus, the carrier employed may be, for example, either a solid or liquid. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders. Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
Examples of oral solid dosage forms include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500 mg. Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like. Examples of injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.
For the methods of treatment disclosed herein, dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors. An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses. An example of a suitable parenteral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection. An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day. An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.
The examples which follow illustrate the compounds that can be synthesized but they are not limited by the compounds in the tables nor by any particular substituents employed in the schemes for illustrative purposes.
The compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds. The non-limiting examples that follow are illustrations of the compounds of the instant invention and are not meant to limit the invention in any way.